Extended adverse effects of cyclophosphamide on mouse ovarian function

PURPOSE: Most patients with cancer undergo multiple administrations of anticancer drugs during treatment, resulting in chronic impairment of their reproductive health. As improved treatment options increase cancer survival, it has become increasingly important to address fertility issues in cancer survivors. In this study, we examined the pathophysiological effects of multiple exposures to cyclophosphamide (Cy) on the ovaries of mice and their underlying molecular mechanism. METHODS: Female C57BL/6 mice were intraperitoneally injected with 100 mg/kg Cy six times over 2 weeks; 4 weeks later, the mice were sacrificed and their ovaries, sera, and oocytes were collected for histological observation, measurement of anti-Müllerian hormone levels, and assessment of oocyte quantity and quality in response to hormonal stimulation. Gene expression changes in Cy-treated ovaries were examined by microarray and bioinformatics analyses. RESULTS: After repeated Cy exposure, the anti-Müllerian hormone level was decreased, and follicle loss and impairments in the quality of oocyte were irreversible. The expression levels of genes involved in folliculogenesis, oogenesis, and zona pellucida glycoprotein transcription displayed sustained alterations in Cy-exposed ovaries even after 4 weeks. CONCLUSION: The adverse effects of Cy on ovarian function and oocytes remained even after chemotherapy was complete. Therefore, strategies to prevent ovarian damage or restore ovarian function after treatment are required to safeguard the fertility of young cancer survivors.